MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Objective— Arterial injury stimulates remodeling responses that, when excessive, lead to stenosis. These responses are influenced by integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand localized to extracellular matrix fibers in the vascular wall. The role of MFAP4 in vascular biology is unknown. We aimed to test the hypothesis that MFAP4 would enhance integrin-dependent VSMC activation. Approach and Results— We produced Mfap4-deficient (Mfap4 −/− ) mice and performed carotid artery ligation to explore the role of MFAP4 in vascular biology in vivo. Furthermore, we investigated the effects of MFAP4 in neointimal formation ex vivo and in primary VSMC and monocyte cultures in vitro. When challenged with carotid artery ligation, Mfap4 −/− mice exhibited delayed neointimal formation, accompanied by early reduction in the number of proliferating medial and neointimal cells, as well as infiltrating leukocytes. Delayed neointimal formation was associated with decreased cross-sectional area of ligated Mfap4 −/− carotid arteries resulting in lumen narrowing 28 days after ligation. MFAP4 blockade prohibited the formation of neointimal hyperplasia ex vivo. Moreover, we demonstrated that MFAP4 is a ligand for integrin &agr;V&bgr;3 and mediates VSMC phosphorylation of focal adhesion kinase, migration, and proliferation in vitro. MFAP4-dependent VSMC activation was reversible by treatment with MFAP4-blocking antibodies and inhibitors of focal adhesion kinase and downstream kinases. In addition, we showed that MFAP4 promotes monocyte chemotaxis in integrin &agr;V&bgr;3–dependent manner. Conclusions— MFAP4 regulates integrin &agr;V&bgr;3–induced VSMC proliferation and migration, as well as monocyte chemotaxis, and accelerates neointimal hyperplasia after vascular injury.

[1]  J. Vestbo,et al.  Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma , 2015, Thorax.

[2]  J. Vestbo,et al.  Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4. , 2015, American journal of physiology. Lung cellular and molecular physiology.

[3]  A. Akhmedov,et al.  PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design. , 2014, European heart journal.

[4]  Y. Bossé,et al.  A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD , 2014, Thorax.

[5]  M. Bennett,et al.  The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro , 2013, Cardiovascular research.

[6]  J. Vestbo,et al.  Localization of Microfibrillar-Associated Protein 4 (MFAP4) in Human Tissues: Clinical Evaluation of Serum MFAP4 and Its Association with Various Cardiovascular Conditions , 2013, PloS one.

[7]  G. Owens,et al.  Smooth muscle cell phenotypic switching in atherosclerosis. , 2012, Cardiovascular research.

[8]  N. Frangogiannis.  Matricellular proteins in cardiac adaptation and disease. , 2012, Physiological reviews.

[9]  A. Hachiya,et al.  Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection , 2011, Scientific reports.

[10]  Saumitra Das,et al.  Interplay between NS3 protease and human La protein regulates translation-replication switch of Hepatitis C virus , 2011, Scientific reports.

[11]  K. Preissner,et al.  Vitronectin in Vascular Context: Facets of a Multitalented Matricellular Protein , 2011, Seminars in thrombosis and hemostasis.

[12]  J. Zweier,et al.  Protandim attenuates intimal hyperplasia in human saphenous veins cultured ex vivo via a catalase-dependent pathway. , 2011, Free radical biology & medicine.

[13]  U. Holmskov,et al.  Ficolins and FIBCD1: soluble and membrane bound pattern recognition molecules with acetyl group selectivity. , 2011, Molecular immunology.

[14]  B. Sitek,et al.  Detection of novel biomarkers of liver cirrhosis by proteomic analysis , 2009, Hepatology.

[15]  Takehiro Nakamura,et al.  Differential gene expression of 36-kDa microfibril-associated glycoprotein (MAGP-36/MFAP4) in rat organs , 2008, Cell and Tissue Research.

[16]  Mei Han,et al.  Blockade of integrin β3–FAK signaling pathway activated by osteopontin inhibits neointimal formation after balloon injury , 2007 .

[17]  Mei Han,et al.  Blockade of integrin beta3-FAK signaling pathway activated by osteopontin inhibits neointimal formation after balloon injury. , 2007, Cardiovascular pathology.

[18]  E. Choi,et al.  Integrin alpha(v)beta(3) as a target in the prevention of neointimal hyperplasia. , 2007, Journal of vascular surgery.

[19]  P. Quax,et al.  Anti–MCP-1 Gene Therapy Inhibits Vascular Smooth Muscle Cells Proliferation and Attenuates Vein Graft Thickening Both In Vitro and In Vivo , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[20]  U. Holmskov,et al.  Microfibril‐associated Protein 4 Binds to Surfactant Protein A (SP‐A) and Colocalizes with SP‐A in the Extracellular Matrix of the Lung , 2006, Scandinavian journal of immunology.

[21]  T. Itano,et al.  36-kDa microfibril-associated glycoprotein (MAGP-36) is an elastin-binding protein increased in chick aortae during development and growth. , 2005, Experimental cell research.

[22]  M. Hupp,et al.  Targeting of αv integrins interferes with FAK activation and smooth muscle cell migration and invasion , 2005 .

[23]  M. Hupp,et al.  Targeting of alpha(v) integrins interferes with FAK activation and smooth muscle cell migration and invasion. , 2005, Biochemical and biophysical research communications.

[24]  A. Zernecke,et al.  Crucial Role of the CCL2/CCR2 Axis in Neointimal Hyperplasia After Arterial Injury in Hyperlipidemic Mice Involves Early Monocyte Recruitment and CCL2 Presentation on Platelets , 2004, Circulation research.

[25]  W. Parks,et al.  &bgr;3-Integrin Mediates Smooth Muscle Cell Accumulation in Neointima After Carotid Ligation in Mice , 2004, Circulation.

[26]  Guido Tarone,et al.  Positional control of cell fate through joint integrin/receptor protein kinase signaling. , 2003, Annual review of cell and developmental biology.

[27]  Shu Chien,et al.  Stent Implantation Activates Akt in the Vessel Wall: Role of Mechanical Stretch in Vascular Smooth Muscle Cells , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[28]  S. Itohara,et al.  Deficiency of Gelatinase A Suppresses Smooth Muscle Cell Invasion and Development of Experimental Intimal Hyperplasia , 2003, Circulation.

[29]  L. Liaw,et al.  Alterations of Arterial Physiology in Osteopontin-Null Mice , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[30]  T. Nakao,et al.  Role of JNK, p38, and ERK in Platelet-Derived Growth Factor–Induced Vascular Proliferation, Migration, and Gene Expression , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[31]  Z. Galis,et al.  Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling , 2002, Circulation research.

[32]  A. Takeshita,et al.  Importance of Monocyte Chemoattractant Protein-1 Pathway in Neointimal Hyperplasia After Periarterial Injury in Mice and Monkeys , 2002, Circulation research.

[33]  W. Fay,et al.  Endogenous Vitronectin and Plasminogen Activator Inhibitor-1 Promote Neointima Formation in Murine Carotid Arteries , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[34]  George A. Stouffer,et al.  The Role of αvβ3 Integrins in Vascular Healing , 2002, Thrombosis and Haemostasis.

[35]  D. Schlaepfer,et al.  The Focal Adhesion Kinase‐‐A Regulator of Cell Migration and Invasion , 2002, IUBMB life.

[36]  S. Tajima,et al.  Expression of 36-kDa microfibril-associated glycoprotein (MAGP-36) in human keratinocytes and its localization in skin. , 2002, Journal of dermatological science.

[37]  G. Stouffer,et al.  The role of alpha(v)beta3 integrins in vascular healing. , 2002, Thrombosis and haemostasis.

[38]  A. Heagerty,et al.  Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-&bgr; Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition , 2001, Circulation.

[39]  K. Abrams,et al.  Inhibition of vascular smooth muscle cell adhesion and migration by c7E3 Fab (abciximab): a possible mechanism for influencing restenosis. , 2000, Cardiovascular research.

[40]  G. Owens,et al.  Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury. , 2000, The Journal of clinical investigation.

[41]  T. Itano,et al.  Ultrastructural Distribution of 36-kD Microfibril-associated Glycoprotein (MAGP-36) in Human and Bovine Tissues , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[42]  M. Runge,et al.  β3 Integrins Are Upregulated After Vascular Injury and Modulate Thrombospondin- and Thrombin-Induced Proliferation of Cultured Smooth Muscle Cells , 1998 .

[43]  P L Weissberg,et al.  Smooth muscle cell heterogeneity: patterns of gene expression in vascular smooth muscle cells in vitro and in vivo. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[44]  M. Runge,et al.  Beta3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells. , 1998, Circulation.

[45]  Amit Kumar,et al.  Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[46]  E. Ruoslahti,et al.  αvβ3 integrin associates with activated insulin and PDGFβ receptors and potentiates the biological activity of PDGF , 1997 .

[47]  G. Davis,et al.  Integrin-mediated reduction in vascular smooth muscle [Ca2+]i induced by RGD-containing peptide. , 1997, The American journal of physiology.

[48]  E. Ruoslahti,et al.  Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. , 1997, The EMBO journal.

[49]  Steven H. Platts,et al.  Vascular Smooth Muscle αvβ3 Integrin Mediates Arteriolar Vasodilation in Response to RGD Peptides , 1996 .

[50]  G. Davis,et al.  Vascular smooth muscle alpha v beta 3 integrin mediates arteriolar vasodilation in response to RGD peptides. , 1996, Circulation research.

[51]  J. Guan,et al.  Stimulation of phosphatidylinositol 3'-kinase association with foca adhesion kinase by platelet-derived growth factor. , 1994, The Journal of biological chemistry.

[52]  D. Adams,et al.  CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury. , 1994, The American journal of pathology.

[53]  W. Edwards,et al.  Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. , 1994, The Journal of clinical investigation.

[54]  H. Hidaka,et al.  Isolation and characterization of a 36-kDa microfibril-associated glycoprotein by the newly synthesized isoquinolinesulfonamide affinity chromatography. , 1994, Biochemical and biophysical research communications.

[55]  R. Kernoff,et al.  Time course and cellular characteristics of the iliac artery response to acute balloon injury. An angiographic, morphometric, and immunocytochemical analysis in the cholesterol-fed New Zealand white rabbit. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[56]  B. Rollins,et al.  JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells. , 1992, Circulation research.

[57]  R. Kobayashi,et al.  Isolation and characterization of a new 36-kDa microfibril-associated glycoprotein from porcine aorta. , 1989, The Journal of biological chemistry.